Hepatic encephalopathy (HE) is a major neuropsychiatric complication caused by chronic
liver disease such as cirrhosis and is characterized by cognitive and motor dysfunction.
The only curative treatment to date remains liver transplantation (LT). Historically, HE
has always been considered to be a reversible metabolic disorder and has therefore been
expected to completely resolve following LT. However, persisting neurological
complications remain a common problem affecting as many as 47% of LT recipients. LT
is a major surgical procedure accompanied by intraoperative stress and confounding
factors, including blood loss and hypotension. We hypothesize, in the setting of minimal
HE (MHE), the compromised brain becomes susceptible to hypotensive insults, resulting
in cell injury and death.
To investigate this hypothesis, six-week bile-duct ligated (BDL) rats with MHE and
respective controls (SHAM) were used. Blood is withdrawn from the femoral artery
(inducing hypovolemia) until a mean arterial pressure of 30, 60 and 90 mmHg
(hypotension) and maintained for 120 minutes. Our results demonstrated that BDL with
following hypotension of 30 and 60 mmHg have a lower neuronal cell count compared to
SHAM-operated animals. Furthermore, we provide evidence neuronal cell death is
occurring due to apoptosis (observed by presence of cleaved caspase-3). In addition,
cerebral blood flow is reduced in BDL rats compared to SHAM-operated controls.
Second objective was to assess the therapeutic potential of the ammonia-lowering agent
ornithine phenylacetate (OP) in preventing hypotension-induced neuronal loss in BDL
rats. OP-treated BDL rats, in addition to lowering blood ammonia, also ameliorated
cognitive function. However, cleaved caspase-3 levels were still elevated in the brains of
OP-treated BDL rats therefore suggesting OP delays the onset of neuronal death in BDL
rats.
Overall, these findings strongly suggest that cirrhotic patients with MHE are more
susceptible to hypotension-induced neuronal cell loss. Moreover, these results suggest a
patient with HE (even MHE), with a “frail brain”, will fare worse during LT
transplantation and consequently result in poor neurological outcome. Combination of
MHE and hypotension may account for the persisting neurological complications
observed in a number of cirrhotic patients following LT. Therefore, MHE, i) should not
be ignored and therefore diagnosed and ii) merits to be treated in order to reduce the risk
of neurological complications occurring post-LT